1,8-annelated quinoline derivatives substituted with carbon-linked triazoles as farnesyl transferase inhibitors

ABSTRACT

This invention comprises the novel compounds of formula (I) 
                         
wherein r, s, A, X, Y 1 , Y 2 , R 1 , R 2 , R 3 , and R 4  have defined meanings, having farnesyl transferase inhibiting activity; their preparation, compositions containing them and their use as a medicine.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the national stage of Application No. PCT/EP02/14089, filed Dec. 11, 2002, which application claims priority from EP 01204989.6 filed Dec. 19, 2001.

The present invention is concerned with novel 1,8-annelated quinoline derivatives substituted with carbon-linked triazoles, the preparation thereof, pharmaceutical compositions comprising said novel compounds and the use of these compounds as a medicine as well as methods of treatment by administering said compounds.

Oncogenes frequently encode protein components of signal transduction pathways, which lead to stimulation of cell growth and mitogenesis. Oncogene expression in cultured cells leads to cellular transformation, characterized by the ability of cells to grow in soft agar and the growth of cells as dense foci lacking the contact inhibition exhibited by non-transformed cells. Mutation and/or overexpression of certain oncogenes are frequently associated with human cancer. A particular group of oncogenes is known as ras, which have been identified in mammals, birds, insects, mollusks, plants, fungi and yeasts. The family of mammalian ras oncogenes consists of three major members (“isoforms”): H-ras, K-ras and N-ras oncogenes. These ras oncogenes code for highly related proteins generically known as p21^(ras). Once attached to plasma membranes, the mutant or oncogenic forms of p21^(ras) will provide a signal for the transformation and uncontrolled growth of malignant tumour cells. To acquire this transforming potential, the precursor of the p21^(ras) oncoprotein must undergo an enzymatically catalyzed farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Therefore, inhibitors of the enzymes that catalyse this modification, i.e. farnesyl transferase, will prevent the membrane attachment of p21^(ras) and block the aberrant growth of ras-transformed tumours. Hence, it is generally accepted in the art that farnesyl transferase inhibitors can be very useful as anticancer agents for tumours in which ras contributes to transformation.

Since mutated oncogenic forms of ras are frequently found in many human cancers, most notably in more than 50% of colon and pancreatic carcinomas (Kohl et al., Science, vol 260, 1834-1837, 1993), it has been suggested that farnesyl tranferase inhibitors can be very useful against these types of cancer.

In EP-0,371,564 there are described (1H-azol-1-ylmethyl) substituted quinoline and quinolinone derivatives, which suppress the plasma elimination of retinoic acids. Some of these compounds also have the ability to inhibit the formation of androgens from progestines and/or inhibit the action of the aromatase enzyme complex.

In WO 97/16443, WO 97/21701, WO 98/40383 and WO 98/49157, there are described 2-quinolinone derivatives, which exhibit farnesyl transferase inhibiting activity. WO 00/39082 describes a class of novel 1,2-annelated quinoline compounds, bearing a nitrogen- or carbon-linked imidazole, which show farnesyl protein transferase and geranylgeranyl transferase inhibiting activity. Other quinolinone compounds having farnesyl transferase inhibiting activity are described in WO 00/12498, 00/12499, 00/47574 and 01/53289.

Unexpectedly, it has been found that the present novel compounds, all having a phenyl substituent on the 4-position of the 1,8-annelated quinolinone moiety bearing a carbon-linked triazole, show farnesyl protein transferase inhibiting activity. The present compounds may have advantage properties with regard to solubility and stability.

SUMMARY OF THE INVENTION

The present invention concerns compounds of formula (I):

or a pharmaceutically acceptable salt or N-oxide or stereochemically isomeric form thereof, wherein

-   r and s are each independently 1, 2 or 3; -   X is oxygen or sulfur; -   -A- is a bivalent radical of formula     —CH═CH—  (a-1)     —CH₂—CH₂—  (a-2)     —CH₂—CH₂—CH₂—  (a-3)     —CH₂—O—  (a-4) or     —CH₂—CH₂—O—  (a-5)     -   wherein optionally one hydrogen atom may be replaced by         C₁₋₄alkyl; -   >Y¹—Y²— is a trivalent radical of formula     >C═CR⁵—  (y-1) or     >CH—CHR⁵—  (y-2),     -   wherein R⁵ is hydrogen, halo or C₁₋₆alkyl; -   R¹ is hydrogen, hydroxy, halo, cyano, nitro, C₁₋₆alkyl,     —(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl,     C₁₋₆alkyloxyC₁₋₆alkyl, trihalomethyl, -C₁₋₆alkyl-NR¹⁴R¹⁵,     C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, trihalomethoxy, C₂₋₆alkenyl,     C₂₋₆alkynyl, —CHO, C₁₋₆alkylcarbonyl, hydroxycarbonyl,     C₁₋₆alkyloxycarbonyl, —CONR¹⁴R¹⁵, —CONR¹⁴—O—C₁₋₆alkyl,     —CONR¹⁴-C₁₋₆alkenyl, —OC(O)R¹⁶, —CR¹⁶═NR¹⁷ or —CR¹⁶═N—OR¹⁷;     -   p is 0, or 2;     -   R¹² and R¹³ are independently hydrogen or C₁₋₆ alkyl and are         independently defined for each iteration of p in excess of 1;     -   R¹⁴ and R¹⁵ are independently hydrogen, C₁₋₆ alkyl or         —(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl; -   two R¹ substituents adjacent to one another on the phenyl ring may     form together a bivalent radical of formula     —O—CH₂—O—  (b-1)     —O—CH₂—CH₂—O—  (b-2)     —O—CH═CH—  (b-3) or     —O—CH₂—CH₂—  (b-4);     -   R¹⁶ and R¹⁷are independently hydrogen, C₁₋₆ alkyl or         —(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl; -   R² is hydrogen, hydroxy, halo, cyano, nitro, C₁₋₆alkyl,     C₁₋₆alkyloxy, trihalomethyl, C₁₋₆alkylthio, di(C₁₋₆alkyl)amino,     -C₁₋₆alkyl-NR¹⁴R¹⁵, trihalomethoxy, C₂₋₆alkenyl, hydroxycarbonyl,     C₁₋₆alkyloxycarbonyl, —CONR¹⁴R¹⁵, —(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl,     cyanoC₁₋₆alkyl, mono- or di-haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl,     C₁₋₆alkyloxyC₁₋₆alkyl, R¹⁶SC₁₋₆alkyl, Het¹C₁₋₆alkyl, Het¹C₁₋₆alkyl     in which the C₁₋₆alkyl moiety is substituted by hydroxy, Het¹SC₁₋₆     alkyl,     -   -C₁₋₆alkylNR¹⁴-C₁₋₆alkyloxyC₁₋₆alkyl, -C₁₋₆         alkylNR¹⁴C₂₋₆alkenyl, -C₁₋₆alkylNR¹⁴C₂₋₆alkynyl,         -C₁₋₆alkylNR¹⁴C₁₋₁₆alkyl-NR¹⁴R¹⁵, -C₁₋₆alkylNR¹⁴C₁₋₆alkyl-Het¹,         -C₁₋₆alkylNR¹⁴C₁₋₆alkylC(O)OC₁₋₆alkyl, C₂₋₆alkynyl, —CHO,         C₁₋₆alkylcarbonyl, —CONR¹⁴-C₁₋₆alkyl-NR¹⁴R¹⁵,         —CONR¹⁴—O-C₁₋₆alkyl, —CONR¹⁴-C₁₋₆alkenyl, —NR¹⁴R¹⁵, —OC(O)R¹⁶,         —CR¹⁶═NR¹⁷, —CR¹⁶═N—OR or —C(NR¹⁸R¹⁹)═NR²⁰; -   two R² substituents adjacent to one another on the phenyl ring may     together form a bivalent radical of formula     —O—CH₂—O—  (b-1),     —O—CH₂—CH₂—O—  (b-2)     —O—CH═CH—  (b-3)     —O—CH₂—CH₂—  (b-4) or     —CH₂—O—CH₂  (b-5);     -   R¹⁶ and R¹⁷ are independently hydrogen, C₁₋₆ alkyl or         —(CR¹²R¹³)_(p)-C₃₋₁₀ocycloalkyl;     -   R¹⁸, R¹⁹ and R²⁰ are independently hydrogen and C₁₋₆alkyl; -   R³ is hydrogen, halo, C₁₋₆alkyl, —(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl,     haloC₁₋₆alkyl, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl,     C₁₋₆alkyloxyC₁₋₆alkyl, hydroxycarbonylC₁₋₆alkyl,     C₁₋₆alkyloxycarbonylC₁₋₆alkyl, -C₁₋₆alkyl-NR¹⁴R¹⁵,     -C₁₋₆alkyl-CONR¹⁴R¹⁵, Het¹, or a radical of formula     —O—R⁶  (c-1)     —NR⁷R⁸  (c-2) or     —N═CR⁶R⁷  (c-3)     -   wherein R⁶ is hydrogen, C₁₋₆alkyl,         —(CR¹²R¹³)_(p)-C₃₋₁₀ocycloalkyl, a group of formula —NR¹⁴R¹⁵ or         -C₁₋₆alkylC(O)OC₁₋₆alkyl NR¹⁴R¹⁵, or a radical of formula         -Alk-OR⁹ or -Alk-NR¹⁰R¹¹;     -   R⁷ is hydrogen, C₁₋₆alkyl, —(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl;     -   R⁸ is hydrogen, hydroxy, C₁₋₆alkyl,         —(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl, C₁₋₆alkylcarbonylamino,         C₁₋₆alkylcarbonyl, haloC₁₋₆alkylcarbonyl, Ar¹C₁₋₆alkylcarbonyl,         Het¹C₁₋₆alkylcarbonyl, Ar¹carbonyl, C₁₋₆alkyloxycarbonyl,         trihaloC₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxyC₁₋₆alkylcarbonyl,         aminocarbonyl, mono- or di(C₁₋₆alkyl)aminocarbonyl wherein the         alkyl moiety may optionally be substituted by one or more         substituents independently selected from Ar¹ and         C₁₋₆alkyloxycarbonyl substituents; aminocarbonylcarbonyl, mono-         or di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, or a radical of formula         -Alk-OR⁹ or Alk-NR¹⁰R¹¹; wherein Alk is C₁₋₆alkanediyl;     -   R⁹ is hydrogen, C₁₋₆alkyl, —(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl;     -   R¹⁰ is hydrogen, C₁₋₆alkyl, —(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl;     -   R¹¹ is hydrogen, C₁₋₆alkyl, —(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl;     -   R⁴ is hydrogen or C₁₋₆alkyl;     -   Ar¹ is phenyl, naphthyl or phenyl, or naphthyl substituted by         one to five substituents each independently selected from halo,         hydroxy, cyano, nitro, amino, C₁₋₆alkyl, haloC₁₋₆alkyl,         -alkylNR¹⁴R¹⁵, C₁₋₆alkyloxy, OCF₃, hydroxycarbonyl,         C₁₋₆alkyloxycarbonyl, aryloxy, —NR¹⁴R¹⁵, C₁₋₆alkylsulfonylamino,         oxime or phenyl, or a bivalent substituent of formula —O—CH₂—O—         or —O—CH₂—CH₂—O—;     -   Het¹ is a mono- or bi-cyclic heterocyclic ring containing one or         more heteroatoms selected from oxygen, sulphur and nitrogen and         optionally substituted by one or two substituents each         independently selected from halo, hydroxy, cyano, nitro,         C₁₋₆alkyl, haloC₁₋₆alkyl, -alkylNR¹⁴R¹⁵, C₁₋₆alkyloxy, OCF₃,         hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CONR¹⁴R¹⁵, —NR¹⁴R¹⁵,         C₁₋₆alkylsulfonylamino, oxime or phenyl.     -   aryl is phenyl, naphthalenyl, phenyl substituted with one or         more substituents each independently selected from halo,         C₁₋₆alkyl, C₁₋₆alkyloxy, trifluoromethyl, cyano, or         hydroxycarbonyl; or naphtalenyl substituted with one or more         substituents each independently selected from halo, C₁₋₆alkyl,         C₁₋₆alkyloxy, trifluoromethyl, cyano or hydroxycarbonyl;

DETAILED DESCRIPTION OF THE INVENTION

As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C₁₋₂alkyl defines methyl and ethyl; C₁₋₄alkyl includes C₁₋₂alkyl and straight and branched chain saturated hydrocarbon radicals having from 3 to 4 carbon atoms such as, e.g. propyl, butyl, 1-methylethyl, 2-methylpropyl and the like; C₁₋₆alkyl includes C₁₋₄alkyl and the higher homologues thereof having 5 to 6 carbon atoms such as, for example, pentyl, 2-methyl-butyl, hexyl, 2-methylpentyl and the like; C₁₋₆alkanediyl defines bivalent straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the branched isomers thereof; haloC₁₋₆alkyl defines C₁₋₆alkyl containing one or more halo substituents for example trifluoromethyl; C₂₋₆alkenyl defines straight and branched chain hydrocarbon radicals containing one double bond and having from 2 to 6 carbon atoms such as, for example, ethenyl, 2-propenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, and the like.

The pharmaceutically acceptable salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms, which the compounds of formula (I) are able to form. The compounds of formula (I) which have basic properties can be converted in their pharmaceutically acceptable acid addition salts by treating said base form with an appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-amino-salicylic, pamoic and the like acids.

The compounds of formula (I) which have acidic properties may be converted in their pharmaceutically acceptable base addition salts by treating said acid form with a suitable organic or inorganic base. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.

The term “acid or base addition salts” also comprises the hydrates and the solvent addition forms, which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.

Compounds of formula (I) can be in the zwitterion form.

The term stereochemically isomeric forms of compounds of formula (I), as used hereinbefore, defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms, which said compound might possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of formula (I) both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.

Some of the compounds of formula (I) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.

Wherever -A- is a bivalent radical of formula (a-4) or (a-5), the CH2 moiety in said bivalent radical is preferably connected to the nitrogen atom of the 2-quinolinone-moiety of the compounds of formula (I) or the intermediates of formula (II).

Whenever used hereinafter, the term “N-imidazolyl” means that the imidazolyl is attached to the rest of the molecule through a nitrogen atom.

Whenever used hereinafter, the term “compounds of formula (I)” is meant to include also the pharmaceutically acceptable acid and base addition salts and all stereoisomeric forms.

A group of interesting compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply;

-   a) r and s are each independently 1 -   b) X is oxygen; -   c) -A- is a bivalent radical of formula (a-2) or (a-3); -   d) >Y¹—Y²— is a trivalent radical of formula (y-1) wherein R⁵ is     hydrogen; -   e) R¹ is halo, C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl; -   f) R² is halo, cyano, nitro, C₁₋₆alkyl, cyanoC₁₋₆alkyl,     hydroxyC₁₋₆alkyl or Het¹C₁₋₆alkyl; -   g) R³ is hydrogen, cyanoC₁₋₆alkyl, -C₁₋₆alkyl-CONH₂, Het¹ or is a     radical of (c-1), (c-2), or (c-3) wherein R⁶ is hydrogen, R⁷ is     hydrogen or C₁₋₆alkyl and R⁸ is hydrogen, hydroxy or C₁₋₆alkyl; -   h) R⁴ is C₁₋₂alkyl.

Another group of interesting compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply;

-   a) r and s are each independently 1; -   b) X is oxygen; -   c) -A- is a bivalent radical of formula (a-2) or (a-3); -   d) >Y¹—Y²— is a trivalent radical of formula (y-1) wherein R⁵ is     hydrogen; -   e) R² is halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl or C₁₋₆alkyloxy; -   f) R² is halo, cyano, C₁₋₆alkyl, cyanoC₁₋₁₆alkyl, hydroxyC₁₋₆alkyl     or Het¹C₁₋₆alkyl; -   g) R³ is hydrogen, cyanoC₁₋₆alkyl, -C₁₋₆alkyl-CONH₂, Het¹ or is a     radical of (c-1), (c-2), or (c-3) wherein R⁶ is hydrogen, R⁷ is     hydrogen or C₁₋₆alkyl and R⁸ is hydrogen, hydroxy or C₁₋₆alkyl; -   h) R⁴ is C₁₋₂alkyl.

A further group of interesting compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply;

-   a) r and s are each independently 1; -   b) X is oxygen; -   c) -A- is a bivalent radical of formula (a-2), (a-3) or (a-4); -   d) >Y¹—Y²— is a trivalent radical of formula (y-1) wherein R⁵ is     hydrogen or halo; -   e) R¹ is halo; -   f) R² is halo or cyano; -   g) R³is hydrogen, hydroxy, amino, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy,     C₁₋₆alkylcarbonylamino or N-imidazolyl; -   h) R⁴ is C₁₋₂alkyl.

A more interesting group of compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply;

-   a) R¹ is 3-chloro, 3-bromo, 3-methyl, or 3-ethyloxy; -   b) R² is in the para-position, or 1N-1,2, 3, 4 tetrazolylC₁₋₆alkyl; -   c) R³ is NH₂ or N-imidazolyl; -   d) R⁴is methyl.

A particular group of compounds consists of those compounds of formula (I) wherein r and s are each independently 1; X is oxygen; -A- is a bivalent radical of formula (a-2); >Y¹Y²- is a trivalent radical of forrnula (y-1) wherein R⁵ is hydrogen; R¹ is halo or C₁₋₆alkyl; R² is halo, cyano, C₁₋₆alkyl or Het¹C₁₋₆alkyl; R³is hydrogen, hydroxy, NH₂ or Het¹; and R⁴ is C₁₋₂alkyl.

A further particular group of compounds consists of those compounds of formula (I) wherein r and s are each independently 1; X is oxygen; -A- is a bivalent radical of formula (a-2); >Y¹—Y²— is a trivalent radical of formula (y-1) wherein R⁵ is hydrogen; R¹ is halo, C₁₋₆alkyl, or C₁₋₆alkyloxy; R² is halo, cyano, C₁₋₆alkyl or Het¹C₁₋₆alkyl; R³ is hydrogen, hydroxy, NH₂ or Het¹; and R⁴is C₁₋₂alkyl.

Preferred compounds are those compounds of formula (I) wherein r and s are each independently 1; X is oxygen; -A- is a bivalent radical of formula (a-2), (a-3) or (a-4); >Y¹—Y²— is a trivalent radical of formula (y-1) wherein R⁵is hydrogen or halo; R¹ is halo; R² is halo or cyano; R³is hydrogen, hydroxy, amino, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, C₁₋₆alkylcarbonylamino or N-imidazolyl; and R⁴ is C₁₋₂alkyl.

Most preferred compounds are

-   6-(3-chlorophenyl)-1,2-dihydro-8-[(4-iodophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-4H-pyrrolo[3,2,1-ij]quinolin-4-one; -   4-[[6-(3-chlorophenyl)-1,2-dihydro-4-oxo-4H-pyrrolo[3,2,1-ij]quinolin-8-yl](4-methyl-4H-1,2,4-triazol-3-yl)methyl]-     benzonitrile; -   7-(3-chlorophenyl)-9-[(4-chlorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-2,3-dihydro-1H,5H-benzo[ij]quinolizin-5-one; -   6-(3-chlorophenyl)-8-[(4-fluorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one; -   6-(4-chlorophenyl)-8-[(4-chlorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one; -   6-(3-bromophenyl)-8-[(4-bromophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one; -   N-[[6-(3-chlorophenyl)-1,2-dihydro-4-oxo-4H-pyrrolo[3,2,1-ij]quinolin-8-yl](4-fluorophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-acetamide; -   7-(3-chlorophenyl)-9-[(4-chlorophenyl)methoxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-2,3-dihydro-1H,5H-benzo[ij]quinolizin-5-one; -   6-(3-chlorophenyl)-8-[(4-fluorophenyl)(2-hydroxyethoxy)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one; -   6-(3-chlorophenyl)-8-[(4-fluorophenyl)-1     H-imidazol-1-yl(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one; -   8-[amino(4-fluorophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-6-(3-chlorophenyl)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one     and their pharmaceutically acceptable salts.

The compounds of formula (I) and their pharmaceutically acceptable salts and N-oxides and stereochemically isomeric forms thereof may be prepared, for example, by the following processes:

-   a) Compounds of formula (I), wherein R⁴ is C₁₋₆alkyl and R³ is     hydroxy, said compounds being referred to as compounds of formula     (I-a), may be prepared by reacting an intermediate ketone of     formula (II) with an intermediate triazole reagent of formula     (III-a) wherein R²¹ is hydrogen or C₁₋₆ alkyl, to form intermediates     of formula (IVa) and subsequently removing the 3-mercapto or the     3-C₁₋₆alkylmercapto group. More in particular, the compounds of     formula (I-a) may be prepared by reacting the compound of     formula (II) with the triazole reagent (III-a), preferably in a     reaction-inert solvent such as tetrahydrofuran, in the presence of a     strong base such as butyl lithium at a temperature ranging from     −78° C. to room temperature. Removal of the 3-mercapto group is     conveniently effected with sodium nitrite, for example in THF/H₂O in     the presence of nitric acid. Removal of, for example, the     3-methylmercapto group is conveniently effected with Raney Nickel in     ethanol or acetone. Another method for obtaining intermediates of     formula (IVa) starting from intermediates of formula (II) is     described in the examples.

-   b) Compounds of formula (I), wherein R⁴ is hydrogen and R³ is     hydroxy, said compounds being referred to as compounds of formula     (I-b), may be prepared by reacting an intermediate ketone of     formula (II) with an intermediate triazole reagent of formula     (III-b) wherein P is an optional protective group such as, for     example, a sulfonyl group, e.g. a dimethylamino sulfonyl group,     which can be removed after the addition reaction. Said reaction     requires the presence of a suitable strong base, such as, for     example, butyl lithium in an appropriate solvent such as     tetrahydrofuran

Compounds of formula (I-a) and (I-b) can optionally be the subject of one or more of the following conversions in any desired order:

-   (i) converting a compound of formula (I) into a different compound     of formula (I); -   (ii) converting a compound of formula (I) into a pharmaceutically     acceptable salt or N-oxide thereof; -   (iii) converting a pharmaceutically acceptable salt or N-oxide of a     compound of formula (I) into the parent compound of formula (I); -   (iv) preparing a stereochemical isomeric form of a compound of     formula (I) or a pharmaceutically acceptable salt or N-oxide     thereof.

Examples of the conversion of one compound of formula (I) into a different compound of formula (I) include the following reactions:

-   a) Compounds of formula (I-c) wherein R³ is hydroxy, can be     converted into compounds of formula (I-d), defined as a compound of     formula (I) wherein R³ is hydrogen, by submitting the compounds of     formula (I-c) to appropriate reducing conditions, such as, e.g.     stirring in acetic acid in the presence of formamide, or treatment     with sodium borohydride/trifluoroacetic acid.

-   b) Compounds of formula (I-c) can be converted to compounds of     formula (I-e) wherein R³ is halo, by reacting the compounds of     formula (I-c) with a suitable halogenating agent, such as, e.g.     thionyl chloride or phosphorus tribromide. Successively, the     compounds of formula (I-e) can be treated with a reagent of formula     H-NR⁷R⁸ in a reaction-inert solvent, thereby yielding compounds of     formula (I-f).

-   c) Compounds of formula (I-c) can be converted into compounds of     formula (I-f), for example, by treatment with SOCl2, and then     NH₃/iPrOH, e.g. in a tetrahydrofuran solvent, or by treatment with     acetic acid ammonium salt at a temperature ranging from 120 to 180°     C., or by treatment with sulfamide at a temperature ranging from 120     to 180° C. -   d) A compound of formula (I-h), defined as a compound of formula (I)     wherein X is sulfur, may be prepared by reacting the corresponding     compound of formula (I-g), defined as a compound of formula (I)     wherein X is oxygen, with a reagent like phosphorus pentasulfide or     Lawesson's reagent in a suitable solvent such as, for example,     pyridine.

-   e) Compounds of formula (I) in which >Y¹—Y² represents a radical of     formula (y-1) can be converted into corresponding compounds of     formula (I) in which >Y¹—Y² represents a radical of formula (y-2) by     conventional reduction procedures, for example, hydrogenation or     reduction by treatment with sodium borohydride in a suitable     solvent, e.g. methanol and vice versa by conventional oxidation     procedures such as, for example, treatment with bromine in an     appropriate solvent such as, e.g. bromobenzene, or treatment with     iodine in the presence of acetic acid and potassium acetate. Said     oxidation reaction can give rise to side-products wherein the     bivalent radical -A- is oxidized. For instance, oxidation of     intermediates of formula (II) in which >Y¹—Y² represents a radical     of formula (y-2), wherein -A- is (a-2) may give intermediates of     formula (II) in which >Y¹—Y² represents a radical of formula (y-1)     wherein -A- is (a-1). -   f) The compounds of formula (I) may also be converted into each     other via art-known reactions or functional group transformations. A     number of such transformations are already described hereinabove.     Other examples are hydrolysis of carboxylic esters to the     corresponding carboxylic acid or alcohol; hydrolysis of amides to     the corresponding carboxylic acids or amines; hydrolysis of nitriles     to the corresponding amides; amino groups on imidazole or phenyl may     be replaced by a hydrogen by art-known diazotation reactions and     subsequent replacement of the diazo-group by hydrogen; alcohols may     be converted into esters and ethers; primary amines may be converted     into secondary or tertiary amines; double bonds may be hydrogenated     to the corresponding single bond; an iodo radical on a phenyl group     may be converted in to an ester group by carbon monoxide insertion     in the presence of a suitable palladium catalyst.

The intermediates and starting materials used in the above-described processes may be prepared in conventional manner using procedures known in the art for example as described in the above-mentioned patent specifications WO 97/16443, WO 97/21701, WO 98/40383, WO 98/49157 and WO 00/39082.

For example intermediates of formula (II) can be prepared by procedures described in International Patent Specification No. WO 98/40383, from page 11 to page 13, or by processes analogous thereto. In addition an intermediate keton of formula (II) can be prepared by reacting an intermediate compound of formula (V) with an intermediate compound of formula (VI) wherein Z represents B(OH)₂ or Sn(C₁₋₄alkyl)₃, and addition of carbon monoxide at atmospheric pressure or at an increased pressure, in the presence of a suitable palladium-catalyst (e.g. palladium on charcoal), an appropriate base such as triethylamine and a suitable solvent such as dioxane.

-   a) Intermediate ketons of formula (II) can also be prepared by     reacting intermediate compounds of formula (VII) with intermediate     compounds of formula (VIII) in the presence of a suitable solvent     such as tetrahydrofuran.

-   b) The intermediate compounds of formula (VII) can be prepared by     reacting intermediate compounds of formula (V) with intermediate     compounds of formula (IX) and addition of carbon monoxide at     atmospheric pressure or at an increased pressure, in the presence of     a suitable palladium-catalyst (e.g. palladium on charcoal), an     appropriate base such as triethylamine and a suitable solvent such     as dioxane.

-   c) The intermediate compounds of formula (V-a) wherein >Y¹—Y²— is a     trivalent radical of formula (y-2) wherein R⁵ is hydrogen can be     converted in intermediate compounds of formula (V-b) wherein     >Y¹—Y²²— is a trivalent radical of formula (y-1) wherein R⁵ is     hydrogen, in the presence of iodium, potassium acetate and a     suitable solvent such as acetic acid.

-   d) Intermediate compounds of formula (V-a) wherein X is oxygen, can     be prepared by reacting intermediate compounds of formula (XI) with     polyphosphoric acid (PPA).

-   e) Intermediate compounds of formula (XI) can be prepared by     reacting intermediate compounds of formula (XII) with intermediate     compounds of formula (XIII) in the presence of an appropriate base     such as triethylamine and a suitable solvent such as dichloromethane     (DCM).

The compounds of formula (I) and some of the intermediates have at least one stereogenic centre in their structure. This stereogenic centre may be present in an R or an S configuration.

The compounds of formula (I) as prepared in the hereinabove described processes are generally racemic mixtures of enantiomers, which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (I) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound would be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.

The compounds of formula (I), the pharmaceutically acceptable acid addition salts and stereoisomeric forms thereof have valuable pharmacological properties in that they have a potent farnesyl protein transferase (FPTase) inhibitory effect.

This invention provides a method for inhibiting the abnormal growth of cells, including transformed cells, by administering an effective amount of a compound of the invention. Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g. loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) expressing an activated ras oncogene; (2) tumor cells in which the ras protein is activated as a result of oncogenic mutation of another gene; (3) benign and malignant cells of other proliferative diseases in which aberrant ras activation occurs. Furthermore, it has been suggested in literature that ras oncogenes not only contribute to the growth of tumors in vivo by a direct effect on tumor cell growth but also indirectly, i.e. by facilitating tumor-induced angiogenesis (Rak. J. et al, Cancer Research, 55, 4575-4580, 1995). Hence, pharmacologically targeting mutant ras oncogenes could conceivably suppress solid tumor growth in vivo, in part, by inhibiting tumor-induced angiogenesis.

This invention also provides a method for inhibiting tumour growth by administering an effective amount of a compound of the present invention, to a subject, e.g. a mammal (and more particularly a human) in need of such treatment. In particular, this invention provides a method for inhibiting the growth of tumours expressing an activated ras oncogene by the administration of an effective amount of the compounds of the present invention. Examples of tumours which may be inhibited, but are not limited to, lung cancer (e.g. adenocarcinoma and including non-small cell lung cancer), pancreatic cancers (e.g. pancreatic carcinoma such as, for example exocrine pancreatic carcinoma), colon cancers (e.g. colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), prostate cancer including the advanced disease, hematopoietic tumours of lymphoid lineage (e.g. acute lymphocytic leukemia, B-cell lymphoma, Burkitt's lymphoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), tumours of mesenchymal origin (e.g. fibrosarcomas and rhabdomyosarcomas), melanomas, teratocarcinomas, neuroblastomas, gliomas, benign tumour of the skin (e.g. keratoacanthomas), breast carcinoma (e.g. advanced breast cancer), kidney carcinoma, ovary carcinoma, bladder carcinoma and epidermal carcinoma.

This invention may also provide a method for inhibiting proliferative diseases, both benign and malignant, wherein ras proteins are aberrantly activated as a result of oncogenic mutation in genes. With said inhibition being accomplished by the administration of an effective amount of the compounds described herein, to a subject in need of such a treatment. For example, the benign proliferative disorder neuro-fibromatosis, or tumours in which ras is activated due to mutation or overexpression of tyrosine kinase oncogenes, may be inhibited by the compounds of this invention.

The compound according to the invention can be used for other therapeutic purposes, for example:

-   -   a) the sensitisation of tumours to radiotherapy by administering         the compound according to the invention before, during or after         irradiation of the tumour for treating cancer, for example as         described in WO 00/01411;     -   b) treating athropathies such as rheumatoid arthritis,         osteoarthritis, juvenile arthritis, gout, polyarthritis,         psoriatic arthritis, ankylosing spondylitis and systemic lupus         erythematosus, for example as described in WO 00/01386;     -   c) inhibiting smooth muscle cell proliferation including         vascular proliferative disorders, atherosclerosis and         restenosis, for example as described in WO 98/55124;     -   d) treating inflammatory conditions such as ulcerative colitis,         Crohn's disease, allergic rhinitis, graft vs host disease,         conjunctivitis, asthma, ARDS, Behcets disease, transplant         rejection, uticaria, allergic dermatitis, alopecia areata,         scleroderma, exanthem, eczema, dermatomyositis, acne, diabetes,         systemic lupus erythematosis, Kawasaki's disease, multiple         sclerosis, emphysema, cystic fibrosis and chronic bronchitis;     -   e) treating endometriosis, uterine fibroids, dysfunctional         uterine bleeding and endometrial hyperplasia;     -   f) treating ocular vascularisation including vasculopathy         affecting retinal and choroidal vessels;     -   g) treating pathologies resulting from heterotrimeric G protein         membrane fixation including diseases related to following         biological functions or disorders; smell, taste, light,         perception, neurotransmission, neurodegeneration, endocrine and         exocrine gland functioning, autocrine and paracrine regulation,         blood pressure, embryogenesis, viral infections, immunological         functions, diabetes, obesity;     -   h) inhibiting viral morphogenesis for example by inhibiting the         prenylation or the post-prenylation reactions of a viral protein         such as the large delta antigen of hepatitis D virus; and the         treatment of HIV infections;     -   i) treating polycystic kidney disease;     -   j) suppressing induction of inducible nitric oxide including         nitric oxide or cytokine mediated disorders, septic shock,         inhibiting apoptosis and inhibiting nitric oxide cytotoxicity;     -   k) treating malaria.

The compounds of present invention may be particularly useful for the treatment of proliferative diseases, both benign and malignant, wherein the K-ras B isoform is activated as a result of oncogenic mutation.

Hence, the present invention discloses the compounds of formula (I) for use as a medicine as well as the use of these compounds of formula (I) for the manufacture of a medicament for treating one or more of the above mentioned conditions.

For the treatment of the above conditions, the compound of the invention may be advantageously employed in combination with one or more other medicinal agents such as anti-cancer agents for example selected from platinum coordination compounds for example cisplatin or carboplatin, taxane compounds for example paclitaxel or docetaxel, camptothecin compounds for example irinotecan or topotecan, anti-tumour vinca alkaloids for example vinblastine, vincristine or vinorelbine, anti-tumour nucleoside derivatives for example 5-fluorouracil, gemcitabine or capecitabine, nitrogen mustard or nitrosourea alkylating agents for example cyclophosphamide, chlorambucil, carmustine or lomustine, anti-tumour anthracycline derivatives for example daunorubicin, doxorubicin or idarubicin; HER2 antibodies for example trastzumab; and anti-tumour podophyllotoxin derivatives for example etoposide or teniposide; and antiestrogen agents including estrogen receptor antagonists or selective estrogen receptor modulators preferably tamoxifen, or alternatively toremifene, droloxifene, faslodex and raloxifene, or aromatase inhibitors such as exemestane, anastrozole, letrazole and vorozole.

For the treatment of cancer the compounds according to the present invention can be administered to a patient as described above, in conjunction with irradiation. Such treatment may be especially beneficial, as farnesyl transferase inhibitors can act as radiosensitisers, for example as described in International Patent Specification WO 00/01411, enhancing the therapeutic effect of such irradiation.

Irradiation means ionizing radiation and in particular gamma radiation, especially that emitted by linear accelerators or by radionuclides that are in common use today. The irradiation of the tumour by radionuclides can be external or internal.

Preferably, the administration of the farnesyl transferase inhibitor commences up to one month, in particular up to 10 days or a week, before the irradiation of the tumour. Additionally, it is advantageous to fractionate the irradiation of the tumour and maintain the administration of the farnesyl transferase inhibitor in the interval between the first and the last irradiation session.

The amount of farnesyl protein transferase inhibitor, the dose of irradiation and the intermittence of the irradiation doses will depend on a series of parameters such as the type of tumour, its location, the patient's reaction to chemo- or radiotherapy and ultimately is for the physician and radiologists to determine in each individual case.

The present invention also concerns a method of cancer therapy for a host harboring a tumour comprising the steps of

-   -   administering a radiation-sensitizing effective amount of a         farnesyl protein transferase inhibitor according to the         invention before, during or after     -   administering radiation to said host in the proximity to the         tumour.

In view of their useful pharmacological properties, the subject compounds may be formulated into various pharmaceutical forms for administration purposes.

To prepare the pharmaceutical compositions of this invention, an effective amount of a particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets.

Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, to aid solubility for example, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause a significant deleterious effect to the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment.

It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient, calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.

Those skilled in the art could easily determine the effective amount from the test results presented hereinafter. In general it is contemplated that a therapeutically effective amount would be from 0.001 mg/kg to 100 mg/kg body weight, and in particular from 0.1 mg/kg to 100 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 0.1 to 500 mg, and in particular 10 mg to 500 mg of active ingredient per unit dosage form.

The following examples are provided for purposes of illustration.

Hereinafter “THF” means tetrahydrofuran, “DME” means 1,2-dimethoxyethane, “EtOAc” means ethyl acetate, “eq” means equivalent, “DCM” means dichloromethane, “DMF” means dimethylformamide and “BuLi” means n-butyl lithium.

A. Preparation of the Intermediates

EXAMPLE A1

-   a) A mixture of     (±)-6-(3-chlorophenyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one     (described in International Application WO98/40383) (0.211 mol) in     polyphosporic acid (600 g) was stirred at 140° C. overnight.     4-lodo-benzoic acid (0.422 mol) was added portionwise. The mixture     was stirred at 140° C. overnight then brought to 100° C. and poured     out into ice water. DCM was added. The precipitate was filtered over     celite and washed with DCM. The filtrate was extracted with DCM. The     organic layer was basified with K₂CO₃ (10%) then washed with water,     dried (MgSO₄), filtered, and the solvent was evaporated. The residue     was purified by column chromatography over silica gel (15-35 μm)     (eluent: CH₂Cl₂/EtOAc; 95/5). The pure fractions were collected and     the solvent was evaporated, yielding 35 g (32%). A part of this     fraction (1 g) was crystallized from CH₃CN/2-propanone (warm). The     precipitate was filtered off and dried under a vacuo, yielding 0.77     g of     6-(3-chlorophenyl)-1,2,5,6-tetrahydro-8-(4-iodobenzoyl)-4H-pyrrolo[3,2,1-ij]quinolin-4-one,     melting point 275° C. (intermediate 1). -   b) Acetic acid, potassium salt (0.22 mol) then iodine (0.147 mol)     were added at room temperature to a solution of (intermediate 1)     (0.061 mol) in acetic acid (300 ml). The mixture was stirred at     130° C. for 72 hours, poured out into Na₂S₂O₃ 1 M/ice and extracted     with DCM. The organic layer was washed with K₂CO₃ 10%, separated,     dried (MgSO₄), filtered, and the solvent was evaporated. The residue     was purified by column chromatography over silica gel (20-40     μm)(eluent: CH₂Cl₂/CH₃OH;95/5 to 60/40). Two fractions were     collected and the solvent was evaporated. Yielding: 4.0 g of     starting material and 26.5 g F1 (84%). A part (0.7 g) of F1 was     crystallized from 2-propanone. The precipitate was filtered off and     dried, yielding 0.61 g of     6-(3-chlorophenyl)-1,2-dihydro-8-(4-iodobenzoyl)-4H-pyrrolo[3,2,1-ij]quinolin-4-one,     melting point 202° C. (intermediate 2). -   c) A mixture of (intermediate 2) (0.0219 mol) and tosylmethyl     isocyanide (0.0284 mol) was added at −5° C. to DME (330 ml) under N₂     flow. Ethanol (33 ml) then 2-methyl,2-propanol potassium salt     (0.0525 mol) was added portionwise at 5° C. The mixture was stirred     at 10° C. for 1 hour and 30 minutes, poured out into ice water and     extracted with EtOAc. The organic layer was separated, dried     (MgSO₄), filtered, and the solvent was evaporated. The residue was     purified by column chromatography over silica gel (15-35 μm)     (eluent: toluene/EtOAc; 50/50). The pure fractions were collected     and the solvent was evaporated, yielding: 1.9 g of     6-(3-chlorophenyl)-1,2-dihydro-α-(4-iodophenyl)-4-oxo-4H-pyrrolo[3,2,1-ij]quinoline-8-acetonitrile     (intermediate 3). -   d) A mixture of (intermediate 3) (0.0195 mol) in acetic acid (30     ml), sulfuric acid (30 ml) and water (30 ml) was stirred and     refluxed overnight and poured out into ice water. The precipitate     was filtered, washed with diethyl ether and dried under a vaccuo,     yielding (quantitative)     6-(3-chlorophenyl)-1,2-dihydro-α-(4-iodophenyl)-4-oxo-4H-pyrrolo[3,2,1-ij]quinoline-8-acetic     acid (intermediate 4). -   e) N′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine,     monohydrochloride (0.021 mol), 1-hydroxybenzotriazole (0.021 mol)     then N-methyl-hydrazinecarbothioamide (0.021 mol) were added to a     mixture of (intermediate 4) (0.017 mol) in THF (95 ml). The mixture     was stirred at room temperature for 48 hours and poured out into ice     water. The precipitate was filtered off and dried, yielding 8.9 g     (83%) of 6-(3-chlorophenyl)-1,2-dihydro-α-(4-iodophenyl)-4-oxo-,     2-[(methylamino)carbonothioyl]hydrazide     4H-pyrrolo[3,2,1-ij]quinoline-8-acetic acid (intermediate 5). The     product was used without further purification in the next reaction     step. -   f) CH₃ONa (30%) in methanol (0.0133 mol) was added to a mixture of     (intermediate 5) (0.0133 mol) in methanol (110 ml). The mixture was     stirred and refluxed for 3 hours then cooled, poured out into ice     water and extracted with DCM. The organic layer was separated, dried     (MgSO₄), filtered, and the solvent was evaporated. The residue was     purified by column chromatography over silica gel (15-40 μm)     (eluent: CH₂Cl₂/CH₃OH/NH₄OH; 95/5/0.1). The pure fractions were     collected and the solvent was evaporated, yielding 4.35 g (53.5%) of     6-(3-chlorophenyl)-1,2-dihydro-8-[(4-iodophenyl)(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)methyl]-4H-pyrrolo[3,2,1-ij]quinolin-4-one     (intermediate 6).

EXAMPLE A2

n-BuLi (0.0166 mol) was added slowly at −78° C. to a solution of 2,4-dihydro-4-methyl-3H-1,2,4-triazole-3-thione (0.0082 mol) in THF (50 ml) under N₂ flow. The mixture was stirred at 0° C. for 1 hour, then cooled to −78° C. 9-(4-chlorobenzoyl)-7-(3-chlorophenyl)-2,3-dihydro-1H,5H-benzo[ij]quinolizin-5-one (described in International Application WO98/40383) (0.0046 mol) was added portionwise. The mixture was stirred at room temperature for 4 hours, poured out on ice and extracted with EtOAc. The organic layer was separated, dried (MgSO₄), filtered, and the solvent was evaporated. The residue (2.32 g) was purified by column chromatography over silica gel (15-40 μm) (eluent: CH₂Cl₂/CH₃OH/NH₄OH 98/2/0.1 to 96/4/0.1). The pure fractions were collected and the solvent was evaporated. The residue (1 g, 40%). was crystallized from acetonitril. The precipitate was filtered off and dried, yielding 0.52 g (21%) of 7-(3-chlorophenyl)-9-[(4-chlorophenyl)hydroxy(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)methyl]-2,3-dihydro-1H,5H-benzo[ij]quinolizin-5-one hydrate (1:1), melting point 160° C. (intermediate 7).

EXAMPLE A3

-   a) Triethylamine (0.05 mol) was added to a mixture of     5-bromo-2,3-dihydro-1H-indole (0.025 mol) in DCM (35 ml). A solution     of 3-(3-chlorophenyl)-2-propenoyl chloride (0.0365 mol) in DCM     (20 ml) was added dropwise. The mixture was stirred at room     temperature overnight. Water was added. The mixture was extracted     with DCM. The organic layer was separated, dried (MgSO₄), filtered,     and the solvent was evaporated. The residue (11.34 g) was dissolved     in DCM and crystallized from diethyl ether. The precipitate was     filtered off and dried to give 3.17 g of intermediate 8. The     filtrate was evaporated. The residue was dissolved in DCM and     crystallized from diethyl ether. The precipitate was filtered off     and dried, yielding 2.17 g (59%) of     5-bromo-1-[(2E)-3-(3-chlorophenyl)-1-oxo-2-propenyl]-2,3-dihydro-1H-indole     (intermediate 8). -   b) A mixture of intermediate 8 (0.012 mol) and polyphosporic acid     (60 g) was stirred at 140° C. overnight, poured out into ice water     and NH₄OH and extracted with DCM. The organic layer was separated,     dried (MgSO₄), filtered, and the solvent was evaporated. The residue     (5.09 g) was purified by column chromatography over silica gel     (20-45 μm) (eluent: cyclohexane/EtOAc 60/40). The pure fractions     were collected and the solvent was evaporated, yielding 1.7 g of     8-bromo-6-(3-chlorophenyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one     (intermediate 9). -   c) I₂ (0.0112 mol) and potassium acetate (0.0169 mol) were added to     a solution of intermediate 9 (0.0047 mol) in acetic acid (12 ml).     The mixture was stirred at 140° C. for 2 days. After the first     night, 12 (0.584 g, 0.5 eq) and potassium acetate (0.345 g, 0.75 eq)     were added. The mixture was poured out into ice water and NaHSO₃.     The precipitate was filtered. DCM was added to the filtrate. The     mixture was extracted with DCM. The organic layer was washed with     H₂O/NH₄OH, dried (MgSO₄), filtered and the solvent was evaporated.     The residue (2.4 g) was purified by column chromatography over     silica gel (35-70 μm)(eluent: CH₂Cl₂/CH₃OH 98/2). The pure fractions     were collected and the solvent was evaporated, yielding 1.38 g (82%)     of     8-bromo-6-(3-chlorophenyl)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one     (intermediate 10). -   d) A mixture of intermediate 10 (0.0025 mol), N-methoxy-methanamine,     hydrochloride (0.0055 mol), Pd(PPh₃)₄ (0.00025 mol) and     triethylamine (0.0124 mol) in dioxane (30 ml) was stirred at 100° C.     for 3 days under a 5 bar pressure of CO and poured out into ice     water. DCM was added. The mixture was filtered over celite and     extracted with DCM. The organic layer was separated, dried (MgSO₄),     filtered, and the solvent was evaporated. The residue (1.71 g) was     purified by column chromatography over silica gel (15-40 μm)     (eluent: CH₂Cl₂/CH₃OH/NH₄OH 97/3/0.1). The pure fractions were     collected and the solvent was evaporated. The residue (0.56 g) was     crystallized from DCM/diethyl ether. The precipitate was filtered     off and dried, yielding 0.159 g of     6-(3-chlorophenyl)-1,2-dihydro-N-methoxy-N-methyl-4-oxo-4H-pyrrolo[3,2,1-ij]quinoline-8-carboxamide,     melting point 162° C. (intermediate 11). -   e) Phenyl-lithium (0.00065 mol) was added at −78° C. to a solution     of intermediate 11 (0.00054 mol) in THF (4 ml) under N₂ flow. The     mixture was stirred at −78° C. for 2 hours. Water and ice were     added. The mixture was extracted with EtOAc. The organic layer was     separated, dried (MgSO₄), filtered, and the solvent was evaporated.     The residue (0.172 g) was purified by column chromatography over     silica gel (10 μm) (eluent: DCM 100). The pure fractions were     collected and the solvent was evaporated, yielding 0.011 g (5%) of     8-benzoyl-6-(3-chlorophenyl)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one     (intermediate 12).

EXAMPLE A4 An Alternative Way for the Preparation of Intermediate 12 Starting from Intermediate 10

A mixture of intermediate 10 (0.00078 mol), phenyl-boronic acid (0.0011 mol), Pd(PPh₃)₄ (0.078 mol) and triethylamine (0.0038 mol) in dioxane (30 ml) was stirred at 100° C. for 4 days under a 5 bar pressure of CO and poured out into ice water. DCM was added. The mixture was filtered over celite. Celite was washed with DCM. The organic layer was separated, dried (MgSO₄), filtered, and the solvent was evaporated.

The residue (0.31 g) was purified by column chromatography over silica gel (10 μm) (eluent: DCM100). The pure fractions were collected and the solvent was evaporated, yielding 0.075 g (25%) of 8-benzoyl-6-(3-chlorophenyl)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (intermediate 12).

EXAMPLE A5

nBuLi 1.6M in hexane (0.0086 mol) was added at −78° C. to a solution of 2,4-dihydro-4-methyl-3H-1,2,4-triazole-3-thione (0.0043 mol) in THF (25 ml) under N₂ flow. The mixture was stirred at 0° C. for 1 hour, then cooled to −78° C. 8-(4-chlorobenzoyl)-6-(3-chlorophenyl)-2H,4H-oxazolo[5,4,3-ij]quinolin-4-one (0.0024 mol) described in International Publication WO98/40383, was added portionwise. The mixture was stirred at room temperature for 4 hours, poured out into ice water and extracted with EtOAc. The organic layer was separated, dried (MgSO₄), filtered, and the solvent was evaporated. The residue (1.38 g) was purified by column chromatography over silica gel (15-40 μm) (eluent: CH₂Cl₂/CH₃OH/NH₄OH97/3/0.1). The pure fractions were collected and the solvent was evaporated. A part of the residue (0.049 g) was purified by column chromatography over silica gel (10 μm) (eluent: CH₂Cl₂/CH₃OH 98/2). The pure fractions were collected and the solvent was evaporated, yielding 0.018 g (1%) of 6-(3-chlorophenyl)-8-[(4-chlorophenyl)hydroxy(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)methyl]-2H,4H-oxazolo[5,4,3-ij]quinolin-4-one, melting point: 193° C. (intermediate 13).

B. Preparation of the Final Compounds

EXAMPLE B1

Sodium nitrite (0.0057 mol) was added at 10° C. to a mixture of nitric acid (10.5 ml) and water (10.5 ml). A mixture of (intermediate 6) (0.0057 mol) in THF (35 ml) was added dropwise. The mixture was stirred at 10° C. for 1 hour, poured out into ice water, basified with K₂CO₃ solid and extracted with EtOAc. The organic layer was separated, dried (MgSO₄), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (15-40 μm) (eluent: CH₂Cl₂/CH₃OH/NH₄OH; 94/6/0.1). The pure fractions were collected and the solvent was evaporated, yielding 1.35 g (37.7%). A part of this fraction (0.55 g) was crystallized from CH₃CN/diethyl ether. The precipitate was filtered off and dried, yielding 0.35 g (10.5%) of 6-(3-chlorophenyl)-1,2-dihydro-8-[(4-iodophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-4H-pyrrolo[3,2,1-ij]quinolin-4-one. hydrate (1:1), melting point 194° C. (compound I). Intermediate 13 can be converted in a similar way into a similar endproduct.

EXAMPLE B2

N₂ was bubbled in a solution of 6-(3-chlorophenyl)-1,2-dihydro-8-[(4-iodophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-4H-pyrrolo[3,2,1-ij]quinolin-4-one, obtained in example B1 (0.002 mol) in DMF (20 ml) for 1 hour. Zn(CN)₂ (0.0031 mol) then Pd(PPh₃)₄ (0.002 mol) were added. The mixture was stirred at 80° C. for 4 hours, cooled, poured out into ice water, filtered over celite and extracted with DCM. The organic layer was separated, dried (MgSO₄), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (15-35 μm)(eluent: CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.1 to 94/6/0.2). The pure fractions were collected and the solvent was evaporated, yielding 0.41 g (41%) of 4-[[6-(3-chlorophenyl)-1,2-dihydro-4-oxo-4H-pyrrolo[3,2,1-ij]quinolin-8-yl](4-methyl-4H-1,2,4-triazol-3-yl)methyl]- benzonitrile, melting point 174° C. (compound 2).

EXAMPLE B3

Nitric acid (2 ml) was added at 0° C. to a solution of sodium nitrite (0.0014 mol) in water (2 ml). The mixture was stirred for 5 minutes. A solution of (intermediate 7) (0.0012 mol) in THF (8 ml) was added dropwise. The mixture was stirred at 0° C. for 1 hour, poured out into K₂CO₃ 10% and extracted with EtOAc. The organic layer was separated, dried (MgSO₄), filtered, and the solvent was evaporated. The residue (1.1 g) was purified by column chromatography over silica gel (15-40 μm) (eluent: CH₂Cl₂/CH₃OH/NH₄OH 94/6/0.2). The pure fractions were collected and the solvent was evaporated. The residue (0.52 g) was crystallized from acetonitrile. The precipitate was filtered off and dried; yielding 0.22 g (33%) of 7-(3-chlorophenyl)-9-[(4-chlorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-2,3-dihydro-1H,5H-benzo[ij]quinolizin-5-one, melting point 183° C. (compound 3).

EXAMPLE B4

Sulfuric acid concentrated (2 drops) was added to a solution of compound 4 6-(3-chlorophenyl)-8-[(4-fluorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (which was made in a similar way as described in example B1) (0.0001 mol) in acetonitrile (1 ml). The mixture was stirred and refluxed overnight. Water and NH₄OH were added. The mixture was extracted with DCM. The organic layer was separated, dried (MgSO₄), filtered, and the solvent was evaporated. The residue (0.056 g) was taken up in DCM. The precipitate was filtered, washed with diethyl ether and dried; yielding 0.054 g (100%) of N-[[6-(3-chlorophenyl)-1,2-dihydro-4-oxo-4H-pyrrolo[3,2,1-ij]quinolin-8-yl](4-fluorophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-acetamide, melting point 196° C. (compound 5).

EXAMPLE B5

Sulfuric acid concentrated (0.3 ml) was added to a mixture of compound 3 (0.0005 mol) in methanol (6 ml). The mixture was stirred and refluxed for 72 hours, poured out into ice water, basified with NH₄OH and extracted with DCM. The organic layer was separated, dried (MgSO₄), filtered, and the solvent was evaporated. The residue (0.268 g) was purified by column chromatography over silica gel (10 μm) (eluent: CH₂Cl₂/CH₃OH 98/2). The pure fractions were collected and the solvent was evaporated, yielding 0.05 g (17%) of 7-(3-chlorophenyl)-9-[(4-chlorophenyl)methoxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-2,3-dihydro-1H,5H-benzo[ij]quinolizin-5-one, melting point 132° C. (compound 6).

EXAMPLE B6

Sulfuric acid concentrated (2 drops) was added to a mixture of compound 4 (which was made in a similar way as described in example B1) (0.0002 mol) in 1,2-ethanediol (1 ml). The mixture was stirred at 125° C. overnight. Water and ice were added. NH₄OH (1 drop) was added. The precipitate was filtered, washed with diethyl ether and dried. The residue (0.118 g) was purified by column chromatography over silica gel (10 μm)(eluent: toluene/iPrOH/NH₄OH 70/29/1). The pure fractions were collected and the solvent was evaporated, yielding 0.058 g (53%) of 6-(3-chlorophenyl)-8-[(4-fluorophenyl)(2-hydroxyethoxy)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one, melting point 138° C. (compound 7).

EXAMPLE B7

A mixture of compound 4 (which was made in a similar way as described in example B1) (0.0002 mol) in 1,3-dimethyl-2-imidazolidinone (0.6 ml) was stirred at room temperature for 10 minutes. Thionyl chloride (0.0008 mol) was added dropwise at room temperature. The mixture was stirred at room temperature for 3 hours and 30 minutes. 4H-imidazole (0.004 mol) was added portionwise. The mixture was stirred at room temperature overnight, poured out into ice water. The precipitate was filtered off and dried, yielding 0.033 g of 6-(3-chlorophenyl)-8-[(4-fluorophenyl)-1H-imidazol-1-yl(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1,2-dibydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (compound 8).

EXAMPLE B8

A mixture of compound 4 (which was made in a similar way as described in example B1) (0.0002 mol) in 1,3-dimethyl-2-imidazolidinone (0.6 ml) was stirred for 10 minutes. Thionyl chloride (0.0008 mol) was added dropwise at room temperature. The mixture was stirred at room temperature for 3 hours and 30 minutes then added dropwise at 5° C. to NH₃/CH₃OH 7N (0.004 mol). The mixture was stirred at room temperature overnight, poured out into ice water and extracted with DCM. The organic layer was separated, dried (MgSO₄), filtered, and the solvent was evaporated. Water was added. The mixture was stirred at room temperature for 1 hour. The precipitate was filtered, washed with diethyl ether and dried. The residue (0.048 g) was taken up in diethyl ether. The precipitate was filtered off and dried. Diethyl ether was added. The mixture was evaporated, yielding 0.034 g of 8-[amino(4-fluorophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-6-(3-chlorophenyl)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (compound 9).

EXAMPLE B9

Benzyltriethylammonium chloride (0.0003 mol) then iodomethane (0.0006 mol) was added to a solution of compound 4 (which was made in a similar way as described in example B1) (0.0004 mol) in THF (2 ml) and NaOH 3N (2 ml). The mixture was stirred at room temperature for 3 days. Water was added. The mixture was extracted with EtOAc. The organic layer was separated, dried (MgSO₄), filtered, and the solvent was evaporated. The residue (0.217 g ) was purified by column chromatography over silica gel (eluent: DCM/evaporated. 10 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.08 g) was crystallized from 2-propanone/DIPE. The precipitate was filtered off and dried. The filtrate was evaporated, yielding 0.04 g (20%) of 6-(3-chlorophenyl)-8-[(4-fluorophenyl)methoxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (compound 10).

Table F-1 and F-2 lists the compounds that were prepared according to one of the above Examples. The following abbreviations were used in the tables: Co. No. stands for Compound Number, Ex. [Xn°] referred to the same method as described in the Xn° example.

TABLE F-1 intermediates

Table F2 Final Compounds

C. PHARMACOLOGICAL EXAMPLE EXAMPLE C.1 “In Vitro Asay for Inhibition of Farnesyl Protein Transferase”

An in vitro assay for inhibition of farnesyl transferase was performed essentially as described in WO 98/40383, pages 33-34. When appropriate, IC₅₀-values (concentration of the drug, needed to reduce the product of the enzymatic reaction, to 50% of the conrol) were computed using probit analysis for graded data (Finney, D. J., Probit Analuses, 2^(nd) Ed. Chapter 10, Graded Responses, Cambridge Univerity Press, Cambridge 1962). Herein (see table F-3) the effects of test compounds are expressed as pIC₅₀ (the negative log value of the IC₅₀-value). Also the intermediate compounds described in the table F-1 show activity in the in vitro assay for inhibition of farnesyl protein transferase.

EXAMPLE C.2 “Ras-Transformed Cell Phenotype Reversion Assay”

The ras-transformed cell phenotype reversion assay was performed essentially as described in WO 98/40383, pages 34-36.

EXAMPLE C.3 “Farnesyl Protein Transferase Inhibitor Secondary Tumour Model”

The farnesyl protein transferase inhibitor secondary tumour model was used as described in WO 98/40383, page 37.

TABLE F-3 Enzyme activity Co. No. pIC50 1 7.669 2 8.695 3 8.087 4 8.239 11 >7 12 <7 13 8.232 5 8.469 6 >7 7 8.403 8 8.416 9 8.526 10 7.533

D. COMPOSITION EXAMPLE Film-Coated Tablets

Preparation of Tablet Core

A mixture of 100 g of a compound of formula (I), 570 g lactose and 200 g starch is mixed well and thereafter humidified with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinyl-pyrrolidone in about 200 ml of water. The wet powder mixture is sieved, dried and sieved again. Then there is added 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil. The whole is mixed well and compressed into tablets, giving 10.000 tablets, each comprising 10 mg of a compound of formula (I).

Coating

To a solution of 10 g methyl cellulose in 75 ml of denaturated ethanol there is added a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane. Then there are added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol 10 g of polyethylene glycol is molten and dissolved in 75 ml of dichloromethane. The latter solution is added to the former and then there are added 2.5 g of magnesium octadecanoate, 5 g of polyvinyl-pyrrolidone and 30 ml of concentrated colour suspension and the whole is homogenated. The tablet cores are coated with the thus obtained mixture in a coating apparatus. 

1. A compound of formula (I):

or a pharmaceutically acceptable salt or N-oxide or stereochemically isomeric form thereof, wherein -A- is a bivalent radical of formula selected from the group consisting of —CH₂—CH₂—; —CH₂—CH₂—CH₂— and —CH₂—O—; >Y¹—Y²—is >C═CR⁵— wherein R⁵ is hydrogen or halo R¹ is selected from the group consisting of hydrogen or halo; R² is selected from the group consisting of hydrogen, halo, or cyano; R³ is selected from the group consisting of hydrogen, N-imidazolyl, —O—R⁶, and —NHR⁸; wherein R⁶ is selected from the group consisting of hydrogen, C₁₋₆alkyl and hydroxyC₁₋₆alkyl; R⁸ is selected from the group consisting of hydrogen and C₁₋₆alkylcarbonyl; and R⁴ is hydrogen or C₁₋₆alkyl.
 2. A compound according to claim 1 in which R² is halo or cyano; R³ is selected from the group consisting of hydrogen, hydroxy, amino, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, C₁₋₆alkylcarbonylamino and N-imidazolyl; and R⁴ is C₁₋₂alkyl.
 3. A compound according to claim 1 selected from the group consisting of: 6-(3-chlorophenyl)-1,2-dihydro-8-[(4-iodophenyl)(4-methyl-4H-1,2,4-triazol-3-yl) methyl]-4H-pyrrolo[3,2,1-ij]quinolin-4-one; 4-[[6-(3-chlorophenyl)-1,2-dihydro-4-oxo-4H-pyrrolo[3,2,1-ij]quinolin-8-yl](4-methyl -4H-1,2,4-triazol-3-yl)methyl]- benzonitrile; 7-(3-chlorophenyl)-9-[(4-chlorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl) methyl]-2,3-dihydro-1H,5H-benzo[iJ]quinolizin-5-one; 6-(3-chlorophenyl)-8-[(4-fluorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl) methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one; 6-(4-chlorophenyl)-8-[(4-chlorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl) methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one; 6-(3-bromophenyl)-8-[(4-bromophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl) methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one; N-[[6-(3-chlorophenyl)-1,2-dihydro-4-oxo-4H-pyrrolo[3,2,1-ij]quinolin-8-yl](4-fluorophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]- acetamide; 7-(3-chlorophenyl)-9-[(4-chlorophenyl)methoxy(4-methyl-4H-1,2,4-triazol-3-yl) methyl]-2,3 -dihydro-1H,5H-benzo[ij]quinolizin-5-one; 6-(3-chlorophenyl)-8-[(4-fluorophenyl)(2-hydroxyethoxy)(4-methyl-4H-1,2,4-triazol -3-yl)methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one; 6-(3-chlorophenyl)-8-[(4-fluorophenyl)-1H-imidazol-1-yl(4-methyl-4H-1,2,4-triazol -3-yl)methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one; 8-[amino(4-fluorophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-6-(3-chlorophenyl )-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one and pharmaceutically acceptable salts thereof.
 4. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim
 1. 5. An intermediate of formula (IVa):

wherein: -A- is a bivalent radical of formula selected from the group consisting of —CH₂—CH₂—; —CH₂—CH₂—CH₂—and —CH₂—O—; >Y¹—Y²—is>>C═CR⁵ is hydrogen or halo; R¹ is selected from the group consisting of hydrogen or halo; R² is selected from the group consisting of hydrogen, halo, or cyano; R⁴ is C₁₋₆alkyl, and R²¹ is hydrogen or C₁₋₆alkyl. 